Hodzic Lab

Didier Hodzic, PhD,

Research

LINC complexes: connecting the nuclear lamina to the cytoskeleton
The nuclear envelope (NE) of mammalian cells is composed of two lipid bilayers, the inner and the outer nuclear membrane (INM and ONM), which are connected at nuclear pores, thus delineating the perinuclear space. The ONM is an extension of the rough endoplasmic reticulum (ER) and the INM adheres to the nuclear lamina, a meshwork of intermediate filaments composed of A- and B-type lamins. Our work is mostly focused on Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) that consist in macromolecular assemblies that span the NE and physically connect the nuclear lamina to different components of the peripheral cytoskeleton. LINC complexes are formed by the direct interaction, within the perinuclear space, between evolutionary-conserved luminal domains of two families of integral transmembrane proteins: Sun proteins and Nesprins (Figure 1).

Sun1 and Sun2 are integral type II transmembrane proteins whose nucleoplasmic regions interact directly with both A- and B-type lamins. The luminal region of Sun1 and Sun2, which protrude into the perinuclear space, contain two coiled-coil domains and a highly conserved C-terminal region of approximately 150 amino acids called the SUN (Sad1 and UNC-84 homology) domain. This domain interacts directly with the evolutionary-conserved KASH domain (Klarsicht/Anc-1/Syne Homology) shared by Nesprin 1, 2, 3 and 4, another family of type II transmembrane proteins whose cytoplasmic region harbors multiple spectrin repeats. While different isoforms of Nesprin display a complex subcellular localization pattern, giant Nesprin 1 (>1MDa) and Nesprin 2 (>700kDa) isoforms are anchored in the ONM and extend as rod-like structures of up to 300-400 nm into the cytoplasm, where they bind F-actin through N-terminal calponin motifs. Nesprin 3 also contains a KASH domain, but its cytoplasmic region is characterized by the presence of a plectin-binding domain. Nesprin 4 also interact with Sun proteins via its KASH domain and interact with molecular motors.

Figure 1:Structure of LINC complexes (See text for details). ABD: Actin-binding domain; PBD: Plectin-binding domain; INM: Inner Nuclear Membrane; ONM: Outer Nuclear Membrane.

The wide variety of cytoplasmic domains (spectrin repeats, actin and plectin binding domains) provided by KASH domain proteins coupled with their alternative splicing, their developmentally-regulated expression and tissue specificity underlie the wide array of physiological functions of SUN/KASH based macromolecular assemblies. Indeed, SUN and KASH domain proteins are involved in nuclear anchorage to the cytoskeleton, nuclear migration, the coupling of the centrosome to the nucleus, chromosome dynamics, cell polarization and cellular tensegrity. These physiological functions are evolutionary-conserved.

For more details, see Razafsky and Hodzic, J Cell Biol, 186(4); 461-72 (2009).

Depiction of LINC complexes. NE: nuclear envelope; PNS: perinuclear space; INM, ONM: inner and outer nuclear membrane, respectively; Green squares: Calponin Homology (CH) domains; blue ovals: spectrin repeats; red ovals: KASH domains.